| First Author | Luo Q | Year | 2022 |
| Journal | Aging Cell | Volume | 21 |
| Issue | 8 | Pages | e13679 |
| PubMed ID | 35909315 | Mgi Jnum | J:334648 |
| Mgi Id | MGI:7331690 | Doi | 10.1111/acel.13679 |
| Citation | Luo Q, et al. (2022) p38alpha-MAPK-deficient myeloid cells ameliorate symptoms and pathology of APP-transgenic Alzheimer's disease mice. Aging Cell 21(8):e13679 |
| abstractText | Alzheimer's disease (AD), the most common cause of dementia in the elderly, is pathologically characterized by extracellular deposition of amyloid-beta peptides (Abeta) and microglia-dominated inflammatory activation in the brain. p38alpha-MAPK is activated in both neurons and microglia. How p38alpha-MAPK in microglia contributes to AD pathogenesis remains unclear. In this study, we conditionally knocked out p38alpha-MAPK in all myeloid cells or specifically in microglia of APP-transgenic mice, and examined animals for AD-associated pathologies (i.e., cognitive deficits, Abeta pathology, and neuroinflammation) and individual microglia for their inflammatory activation and Abeta internalization at different disease stages (e.g., at 4 and 9 months of age). Our experiments showed that p38alpha-MAPK-deficient myeloid cells were more effective than p38alpha-MAPK-deficient microglia in reducing cerebral Abeta and neuronal impairment in APP-transgenic mice. Deficiency of p38alpha-MAPK in myeloid cells inhibited inflammatory activation of individual microglia at 4 months but enhanced it at 9 months. Inflammatory activation promoted microglial internalization of Abeta. Interestingly, p38alpha-MAPK-deficient myeloid cells reduced IL-17a-expressing CD4-positive lymphocytes in 9 but not 4-month-old APP-transgenic mice. By cross-breeding APP-transgenic mice with Il-17a-knockout mice, we observed that IL-17a deficiency potentially activated microglia and reduced Abeta deposition in the brain as shown in 9-month-old myeloid p38alpha-MAPK-deficient AD mice. Thus, p38alpha-MAPK deficiency in all myeloid cells, but not only in microglia, prevents AD progression. IL-17a-expressing lymphocytes may partially mediate the pathogenic role of p38alpha-MAPK in peripheral myeloid cells. Our study supports p38alpha-MAPK as a therapeutic target for AD patients. |
